The research proposals contained in this application are designed to explore in depth new leads which have emerged from our work on endocrine factors participating in the initiation and progress of breast, endometrial, and prostate cancer. New techniques which we have developed will be applied to the study of the biosynthesis, metabolism, biological activity and subcellular mechanism of action of the various endogenous estrogens. The nature of estrogen formation in various tissue sites and its pharmacological modulation will be studied. The diverse activities of the metabolites of estradiol will be used to interpret the biological significance of changes in estradiol metabolism in cancer patients as determined by radiometric procedures. The heterogeneity in estradiol receptors in normal and tumor tissue will be studied by novel methods to identify its physiological significance and clinical relevance. The role of disturbances in estradiol metabolism whether in situ or peripheral and of the tissue estradiol receptors in prostate cancer will be examined in detail. Pharmacological and nutritional induced changes in hormone biosynthesis and disposition will be explored as possible mediators of increased risk for the disease.